Lung cancer is the leading cause of death by cancer in the U.S. Non-small cell lung cancer (NSCLC) comprises over 75 percent of lung cancers diagnosed. Current chemotherapeutic regimens are not effective against NSCLC, with five-year survival rates hovering at a mere 14 percent. Regimens that exploit cancer-specific targets, specifically in and increase therapeutic indices, should enhance the survival rates of patients. We hypothesize that Beta-lapachone (beta-lap), a drug that selectively kills cancer cells with elevated levels of the two-electron reductase, NAD(P)H:quinone oxidoreductase 1 (NQOI), will be an effective agent for use against NSCLC cells that specifically over-express this bioactivating enzyme. Cell death caused by beta-lap is not dependent on cell cycle status, not dependent on p53, pRb, or caspases, and downstream cell death events are consistent with calpain-mediated apoptosis. More importantly, cell death by beta-lap is dependent on NQO1 expression, where NQO1-deficient cells are resistant to the drug, correction of cells with NQO1 restores lethality, and co-administration of dicumarol (an NQO1 inhibitor) prevents lethality. NQOI is typically elevated 4- to greater than 100-fold in human NSCLC, indicating the use of beta-lap for treatment of this disease. Recent development of novel drug delivery methods make it feasible to administer this drug to determine efficacy against NSCLC in animal models. Three aims will test this hypothesis: Aim 1: Evaluate the role of NQO1 in beta-lap-mediated cell death in NSCLC cells, and develop lab correlates for use in future therapy. (Years 1-3). Aim 2: Develop drug vehicles for beta-lap that either deliver the drug locally to the lung, or utilize systemic delivery schemes that allow accumulation of the vehicle-drug complexes within the lung, while offering simultaneous treatment for metastatic disease. (Years 1-5). Aim 3: Compare beta-lap-encoded microparticles developed in Aim 2 for specific delivery to the lung to systemic delivery (i.p.) of HP-beta-cyclodextrin-beta-lap complexes for NQOl-specific lung tumor responses. We will combine these therapies with systemic dicumarol administration for normal tissue protection. (Years 1-5). We have assembled a strong research team with the needed experience to develop novel drug vehicles, image the deposition and delivery of both beta-lap and the vehicle in the lung, and test the hypothesis that beta-lap should be an efficacious agent against NSCLC due to tumor-specific elevation of NQO 1, a bioactivating enzyme specifically needed for novel calpain-mediated cell death responses elicited by beta-lapachone. We will examine the possibility that co-administration of dicumarol can act as an antidote, increasing the anti-tumor efficacy of beta-lap.